Periodic Reporting for period 1 - Golden-ADC (An Insulin-Gold Nanoplatform as Enhanced Antibody-Drug Conjugate Cancer Therapy)
Periodo di rendicontazione: 2024-03-01 al 2025-08-31
Antibody-drug conjugates (ADCs) have emerged as promising therapies by combining the precision targeting abilities of antibodies with the potency of chemotherapy drugs, to directly attack cancer cells and minimize damage to healthy tissue. While ADCs have achieved remarkable success in hematological malignancies, their performance in solid tumors remains constrained by key challenges. These include design challenges, which limit the drug-antibody ratio and the ability to integrate multiple drug types, and delivery challenges, in which pharmacokinetics and tumor barriers limit ADC accumulation and distribution within tumors.
In the framework of the ERC-CoG project, we are developing gold nanoparticles (GNPs) that harness insulin for delivery of large therapeutics, including antibodies, across biological barriers. GNPs’ surface properties enable straightforward conjugation of large and versatile payload combinations, including different antibodies and drugs, to the same particle. We have recently revealed that these insulin-GNPs can be further developed as an ADC nanoplatform. We have revealed that this ‘Golden’-ADC nanoplatform enables simple conjugation of large payloads of multiple antibodies and drug types, shows efficacy in cancer cell models, and enhances in vivo tumor accumulation, together with deep penetration and wide distribution throughout the tumor. In this ERC-PoC research, we tested our Golden-ADC nanoplatform for effective and safe treatment of triple negative breast cancer, due to the potential high benefits that our nanoplatform can provide for this hard-to-treat cancer, which has a long-standing paucity of effective therapies. Within GOLDEN-ADC, we aimed to achieve significant progress in the technology development process, by proof of concept demonstration of efficacy and safety of the Golden-ADC conjugated with multiple drugs in in-vivo triple negative breast cancer models. To achieve business readiness, we aimed to consolidate the IP strategy, undertake a comprehensive market analysis, and develop the business strategy.
In the framework of the ERC-CoG project, we are developing gold nanoparticles (GNPs) that harness insulin for delivery of large therapeutics, including antibodies, across biological barriers. GNPs’ surface properties enable straightforward conjugation of large and versatile payload combinations, including different antibodies and drugs, to the same particle. We have recently revealed that these insulin-GNPs can be further developed as an ADC nanoplatform. We have revealed that this ‘Golden’-ADC nanoplatform enables simple conjugation of large payloads of multiple antibodies and drug types, shows efficacy in cancer cell models, and enhances in vivo tumor accumulation, together with deep penetration and wide distribution throughout the tumor. In this ERC-PoC research, we tested our Golden-ADC nanoplatform for effective and safe treatment of triple negative breast cancer, due to the potential high benefits that our nanoplatform can provide for this hard-to-treat cancer, which has a long-standing paucity of effective therapies. Within GOLDEN-ADC, we aimed to achieve significant progress in the technology development process, by proof of concept demonstration of efficacy and safety of the Golden-ADC conjugated with multiple drugs in in-vivo triple negative breast cancer models. To achieve business readiness, we aimed to consolidate the IP strategy, undertake a comprehensive market analysis, and develop the business strategy.
In this project, we developed an advanced “Golden-ADC” nanoplatform that merges the selectivity of antibody-drug conjugates (ADCs) with the versatility and stability of nanoparticle-technology. The platform was functionalized with antibodies recognizing Trop-2, a clinically validated marker expressed in many TNBC tumors, and with chemotherapeutic payloads commonly used in FDA-approved ADCs. Using a simple and robust conjugation strategy, both antibodies and drugs were stably anchored onto the nanoparticle surface, overcoming the complex design and stability limitations that restrict current ADC technologies. We systematically evaluated the platform’s efficacy and safety in vitro and in vivo. In human TNBC cells, drug-linked nanoparticles demonstrated potent cytotoxicity, and importantly, dual-drug conjugation on a single nanoparticle produced synergistic tumor-cell killing. Mechanistic studies revealed that the drugs were selectively released in the lysosomes of cancer cells, mirroring the intracellular activation process of clinical ADCs but with enhanced control and efficiency. In TNBC tumor-bearing mice, insulin-coated Golden-ADCs achieved deep intratumoral penetration and uniform dissemination, as shown by advanced imaging and quantitative biodistribution analyses. Treatment with the insulin-guided nanoplatform led to marked tumor growth inhibition, with the most pronounced effect observed when both chemotherapies were co-delivered. Remarkably, tumor suppression was achieved in both high- and low-Trop-2–expressing tumors, demonstrating broad applicability beyond antigen-rich cancers. While free drug formulations induced severe toxicity and early mortality, Golden-ADC treatment was well tolerated, with no observable systemic toxicity. Biodistribution studies confirmed minimal cardiac accumulation, addressing a key limitation of conventional ADCs and chemotherapies known for cardiotoxic side effects. Together, these results establish the Golden-ADC nanoplatform as a safe, potent, and broadly applicable next-generation ADC alternative, offering scalable chemistry, multi-payload flexibility, and improved therapeutic precision. Based on these breakthrough preclinical findings, a provisional patent has been filed, and a scientific manuscript is currently in preparation for publication.
This project takes ADC technology to the next level, overcoming current design and delivery challenges of ADCs, and providing high efficacy and safety in TNBC models in vivo. The ability to coat the nanoplatform with insulin, antibodies and multiple chemotherapy types, while keeping their functionality intact, is critical for real-life implementation. These advancements open new possibilities for biopharmaceuticals and therapeutic applications. This project has laid the foundation for a shift in ADC-based therapy for cancer with high translational potential. With proper support, through further research, industry backing, and regulatory frameworks, Golden-ADC has the potential to revolutionize targeted drug delivery for TNBC and beyond.